Bulletin of the American Physical Society
APS March Meeting 2018
Volume 63, Number 1
Monday–Friday, March 5–9, 2018; Los Angeles, California
Session K49: Physics of Genome Organization: From DNA to Chromatin IFocus
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Sponsoring Units: DBIO DPOLY GSNP Chair: Ralf Bundschuh, Ohio State University Room: LACC 511A |
Wednesday, March 7, 2018 8:00AM - 8:36AM |
K49.00001: Nucleosome unwrapping may be easier than you think Invited Speaker: Ralf Bundschuh Nucleosome unwrapping is essential in order to provide access to eukaryotic DNA otherwise tightly wrapped into nucleosomes. Unwrapping several tens of base pairs from one side of the nucleosome is known to require several kT of free energy. Here we show that for a nucleosome that is fixed on both ends such as in the context of higher order chromatin structure, changes in the end-to-end distance by tens of base pairs are possible at a free energy cost of only a few kT due to the entropic contribution of both ends of the nucleosomes unwrapping simultaneously. We derive this result in the context of quantitatively modeling recently published experimental data on nucleosomes attached to a DNA origami caliper and verify our model through analogous experiments on hexasomes, nucleosomes that are missing one of their histone heterodimers. |
Wednesday, March 7, 2018 8:36AM - 8:48AM |
K49.00002: Nuclear Architecture Controls the Timescales of Genomic Interactions Yaojun Zhang, Nimish Khanna, Olga Dudko, Cornelis Murre Many processes in biology, from antibody production to tissue differentiation, require physical contact between distant genomic segments. The segments must find each other quickly despite chromatin packing and the crowded environment of the cell nucleus. What are the consequences of chromatin architecture for the timescales of genomic interactions? To address this question we analyzed 3D genomic trajectories from a novel multi-color imaging approach applied to live pro-B cells. We find that anomalous diffusion in a viscoelastic environment is the dominant mechanism of chromatin motion. We combined molecular dynamics simulations with statistical and polymer physics to reveal some of the principles by which nuclear architecture controls genomic timescales. Specifically, we built a hierarchy of polymer physics models reflecting a spectrum of chromatin configurations, such as loops and loop domains. We established quantitative relationships between spatial and genomic distances of two segments, and between their encounter time and spatial separation. These models provide quantitative, physical interpretations of the observed genomic motion and generate testable predictions regarding the structure-dynamics relationship at different levels of genome organization. |
Wednesday, March 7, 2018 8:48AM - 9:00AM |
K49.00003: Defect-Facilitated Buckling in Supercoiled DNA Sumitabha Brahmachari, Andrew Dittmore, Yasuharu Takagi, Keir Neuman, John Marko We present a statistical-mechanical model for double-helix DNA with a defect, where the defect is characterized by an immobile point on the DNA contour that allows a localized kink. The degree of the kink is controlled by the defect size, such that a larger defect further reduces the energy of a defect-facilitated DNA kink. We find that defects can spatially trap a plectoneme domain via nucleation of a kinked end loop. Our model explains previously-reported magnetic tweezer experiments showing two buckling signatures in supercoiled DNA containing a base-unpaired region [Dittmore et al, Phys. Rev. Lett. (2017)]. Our model also predicts coexistence of multiple states at the second buckling or 'rebuckling' point, which warrants new experimental investigations. |
Wednesday, March 7, 2018 9:00AM - 9:12AM |
K49.00004: Modeling Functional Regulation of Gene Expression from Chromatin Profiles Zhenjia Wang, Chongzhi Zang Chromatin regulation of gene expression plays a critical role in many biological processes including cancer formation and progression. Several experimental techniques including ChIP-seq and DNase/ATAC-seq have been developed to identify genome-wide chromatin profiles. Using chromatin profiles to predict functional DNA elements and transcription factors (TFs) regulating gene expression is an important problem. Here we present Binding Analysis for Regulation of Transcription (BART), a computational method for predicting functional TFs that regulate any given gene set. Using a genomic cis-regulatory profile predicted by MARGE, a regression and semi-supervised learning-based approach for predicting cis-regulatory profiles from a given gene set, BART predicts TFs whose genomic binding profiles are best associated with the cis-regulatory profile, leveraging thousands of publicly available TF ChIP-seq datasets. We show that BART can accurately predict functional TFs from their target genes in several cancer cell systems. Our work demonstrates the power of computational modeling and utilization of public data for quantitative studies in biological systems. |
Wednesday, March 7, 2018 9:12AM - 9:24AM |
K49.00005: Properties of Gene Expression and Chromatin Structure with Mechanically Regulated Transcription Stuart Sevier, Herbert Levine The mechanical properties of transcription have emerged as central elements in our understanding of gene expression. Recent work has been done introducing a simple description of the basic physical elements of transcription where RNA elongation, RNA polymerase (RNAP) rotation and DNA super-coiling are coupled. Here we generalize this framework to accommodate the behavior of many RNAPs operating on multiple genes on a shared piece of DNA. The resulting framework is combined with well-established stochastic processes of transcription resulting in a model which characterizes the impact of the mechanical properties of transcription on gene expression and DNA structure. Transcriptional bursting readily emerges as a common phenomenon with origins in the geometric nature of the genetic system and results in the bounding of gene expression statistics. Properties of a multiple gene system are examined with special attention paid to the role that genome composition (gene orientation, size, and intergenic distance) plays in the ability of genes to transcribe. The role of transcription in shaping DNA structure is examined and the possibility of transcription driven domain formation is discussed. |
Wednesday, March 7, 2018 9:24AM - 9:36AM |
K49.00006: Uncovering the Relation between Inter-Nucleosome Energetics and Supramolecular Chromatin Structure Joshua Moller, Joshua Lequieu, Juan De Pablo The supramolecular structure of chromatin is influenced by inter- and intra-nucleosome interactions. Central to these interactions, the flexible N-terminal domain histone tails have positively-charged sites that facilitate nucleosome interactions. Recent experiments have quantified inter-nucleosome interactions, but with differing results. With this work, we utilize coarse-grained brownian dynamics simulations with enhanced sampling techniques to provide insight into these experiments, and understand how the inter-nucleosome interactions influence chromatin structure. We quantify the anisotropic interaction energy and highlight the discrepancy between prior results through varying salt concentrations and counter-ion condensation effects. We then highlight that the interaction between the H4 tail and the H2A acidic patch introduces asymmetry into the interaction landscape, favoring a left-handed chromatin super-helix motif. To examine the effect of epigenetic modifications, we introduce acetylations to the H4 and H3 tails and assess the resulting energetic interactions. Lastly, we demonstrate how our results can be incorporated into a multi-scale model that can simulate large scale rearrangements of chromatin. |
Wednesday, March 7, 2018 9:36AM - 9:48AM |
K49.00007: Active hydrodynamics of interphase chromatin: coarse-grained modeling and simulations David Saintillan, Achal Mahajan, Michael Shelley, Alexandra Zidovska The 3D spatiotemporal organization of genetic material inside the nucleus remains an open question in cellular biology. During interphase, chromatin fills the cell nucleus in its uncondensed polymeric form, which allows the transcriptional machinery to access DNA. Recent in vivo imaging experiments have cast light on the existence of coherent chromatin motions inside the nucleus, in the form of large-scale correlated displacements on the scale of microns and lasting for seconds. To elucidate the mechanisms for such motions, we have developed a coarse-grained active polymer model where chromatin is represented as a confined flexible chain acted upon by active molecular motors, which perform work and thus exert dipolar forces on the system. Numerical simulations of this model that account for steric and hydrodynamic interactions as well as internal chain mechanics demonstrate the emergence of coherent motions in systems involving extensile dipoles, which are accompanied by large-scale chain reconfigurations and local nematic ordering. Comparisons with experiments show good qualitative agreement and support the hypothesis that long-ranged hydrodynamic couplings between chromatin-associated active motors are responsible for the observed coherent dynamics. |
Wednesday, March 7, 2018 9:48AM - 10:00AM |
K49.00008: Dynamics of Stretched Single DNA and Native Chromatin in Nanoslits JiaWei Yeh, Kylan Szeto, Chia-Fu Chou, Jie-Pan Shen How external forces and confinements are coordinated is a fundamental question for biopolymer stretching in nanofluidics [1-2]. By applying micro-/nanofluidics, we study the dynamics of single DNA molecules and native chromatin fibers in nanofluidic channels. The DNA and chromatin fibers were stretched by attaching to microspheres held at the entrance of a nanoslit with external fields. The force-extension of DNA polymers in the nano-confinement slits was measured and described by using modified wormlike chain models. The DNA global persistence length increased as narrowing down the nanoslit height was provided, which verified the prediction of theories. [3] This device was used to electrophoretically stretch single native chromatin fibers extracted from human cancer cells by attaching the chromatin to microspheres held at the entrance of a nanoslit. To further demonstrate the potential for the device in epigenetics, the histone modification was optically detected. [4] |
Wednesday, March 7, 2018 10:00AM - 10:12AM |
K49.00009: A Unified Computational Framework for Modeling Genome-wide Nucleosome Landscape Hu Jin, Alex Finnegan, Jun Song Nucleosomes form the fundamental building blocks of eukaryotic chromatin. The precise role of DNA sequence in governing the genome-wide distribution of nucleosomes has been controversial. We develop a unified computational framework, based on the statistical mechanics model of one-dimensional hard rods and the cross-entropy method for optimization, for simultaneously learning nucleosome number and nucleosome-positioning energy from genome-wide nucleosome maps. In contrast to other previous studies, our model can predict both in-vitro and in-vivo nucleosome maps in S. cerevisiae. We rigorously quantify the contribution of hitherto-debated sequence features, including G+C content, 10.5-bp periodicity, and poly(dA:dT) tracts, to three distinct aspects of genome-wide nucleosome landscape: occupancy, translational and rotational positioning. Applying our method to in-vivo nucleosome maps further demonstrates that, for a subset of genes, the regularly-spaced nucleosome arrays observed around transcription start sites can be partially recapitulated by DNA sequence alone. Finally, in-vivo nucleosome occupancy derived from MNase-seq experiments around transcription termination sites can be mostly explained by the genomic sequence. [BIORXIV/2017/202580] |
Wednesday, March 7, 2018 10:12AM - 10:24AM |
K49.00010: Dynamic Force-Extension of DNA with Nucleoid Associated Proteins Katelyn Dahlke, Charles Sing Nucleoid associated proteins (NAPs) manipulate the genomic material in prokaryotic cells by manipulating the shape and structure of DNA. These NAPs act by bending or twisting DNA, and there are indications that the binding behavior of NAPs is dependent on the local bend of DNA. These interactions occur in a dynamic cell, where the forces acting on the DNA and the surrounding environment are changing. We predict that the different timescales will result in concentration and force dependent dynamic behaviors. |
Wednesday, March 7, 2018 10:24AM - 10:36AM |
K49.00011: Structure and Dynamics of Histone-DNA Phase Separated Liquid Droplets Anisha Shakya, John King Liquid-liquid phase separation of biological and synthetic polymers due to multivalent interactions is a known problem in polyelectrolyte physics. Currently there is a revived interest in fully understanding this phenomenon as its importance to cell biology has become increasingly clear. Here, we show that histones, owing to their intrinsically disordered regions, phase separate into highly dynamic liquid droplets in the presence of DNA. We also employ state-of-the-art super-resolved fluorescence microscopy techniques to gain unique access into the nanoscopic structural organization and dynamics of the liquid droplets. We find that the diffusive dynamics of small molecules within histone-DNA liquid droplets is non-Fickian (subdiffusive). Such transport mechanism can have significant implications in genome biology, in particular transcription kinetics and regulation of chromatin. |
Wednesday, March 7, 2018 10:36AM - 10:48AM |
K49.00012: Unexpected Discontinuous Supercoiling of Torsionally Buckled DNA: Evidence for a Solenoid? Andrew Dittmore, Keir Neuman Overtwisted elastic rods are known to buckle into a coiled loop (a plectoneme) to relieve torsional stress. This buckling event is marked by a discontinuous drop in the extension of a single supercoiled DNA molecule, as observed in experiments. Contrary to expectations and current models, we observe a subsequent cascade of highly regular discontinuous extension changes during plectoneme extrusion, indicating a series of kinetic barriers. We reconcile these data within the context of elastic rod theory and present a self-consistent model in which the extended DNA adopts a solenoid structure. In this scenario, kinetic barriers to plectoneme extension arise from boundary matching conditions between the solenoid and the plectoneme. Although evidence for a solenoid has not been previously reported for DNA, extended solenoids have been imaged in actin filaments which bend and form superstructures on a much larger characteristic length scale. Our data and model provide a framework for further measurements and theories that capture the structures and mechanics of supercoiled biopolymers. |
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